1. Field of the Invention
This invention relates to certain pyrazolo[4,3-d]pyrimidine derivatives which selectively bind to corticotropin-releasing factor (CRF) receptors. More specifically, the invention relates to 3-aryl substituted pyrazolo[4,3-d]pyrimidine derivatives. The invention further relates to pharmaceutical compositions comprising such compounds. It also relates to the use of such compounds in treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety.
2. Description of the Related Art
International Application PCT/US93/11333 describes pyrazolo[3,4-d]pyrimidines said to be CRF antagonists. Bull. Chem. Soc. Japan. 52(1), 208-11, (1979) describes the synthesis of 3-phenyl-pyrazolo[4,3-d]pyrimidines.
This invention provides novel compounds of Formula I which interact with CRF receptors.
The invention provides pharmaceutical compositions comprising compounds of Formula I. It further relates to the use of such compounds in treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety. Accordingly, a broad embodiment of the invention is directed to a compound of Formula I: 
wherein
Ar is phenyl, 1- or 2- naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3- thienyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy, provided that at least one of the positions on Ar ortho to the point of attachment to the pyrazole ring is substituted;
R1 is lower alkyl;
R2 is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy having 1-6 carbon atoms;
R3 and R4 are the same or different and represent hydrogen, lower alkyl, alkoxy lower alkyl, hydroxy lower alkyl, or alkenyl;
phenyl, 2-, 3-, or 4- pyridinyl, 2- or 3-thienyl or 2-, 4- or 5-pyrimidinyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy;
phenyl-, 2-, 3-, or 4-pyridinyl-, 2- or 3-thienyl-, or 2-, 4- or 5-pyrimidinyl-lower alkyl, each of which is optionally mono- or disubstituted with lower alkyl;
cycloalkyl or cycloalkyl lower alkyl, each of which is optionally mono- or disubstituted with lower alkyl; or
2-hydroxyethyl or 3-hydroxypropyl, each of which is optionally monosubstituted with lower alkyl;
provided that not both R3 and R4 are hydrogen; or
R3 and R4 taken together represent xe2x80x94(CH2)nxe2x80x94Axe2x80x94(CH2)mxe2x80x94 where
n is 2, or 3;
A is methylene, 1,2-phenylene, oxygen. sulfur or NR6, wherein R6 is lower alkyl, phenyl, 2-, 3-, or 4-pyridinyl, 2-or 3-thienyl or 2-, 4- or 5-pyrimidinyl, or phenyl-, 2-, 3-or 4-pyridinyl-, 2-or 3-thienyl-, or 2-, 4- or 5-pyrimidinylalkyl; and
m is 1,2 or 3.
These compounds are highly selective partial agonists or antagonists at CRF receptors and are usefuil in the diagnosis and treatment of stress related disorders such as post traumatic stress disorder (PTSD) as well as depression and anxiety.